Spinal muscular atrophy (SMA) is a rare genetic disease caused by the progressive loss of motor neurons, the specialized nerve cells that control voluntary movements, leading to muscle weakness and wasting.
Due to the progressive nature of SMA, an earlier diagnosis is particularly important in terms of treatment: The sooner therapies are initiated, the higher are the chances that they will slow or even prevent motor neuron loss and overall disease progression.
If a person shows common SMA symptoms and/or has a family history of the disease, further tests should be conducted so as to enable such a diagnosis.
Given the variability of symptoms across the different types of SMA, as well as some similarities with other conditions, genetic testing is the standard — and most accurate — method for a conclusive diagnosis of the disease.
Moreover, such DNA testing also is highly reliable in identifying individuals who are carriers of SMA. These individuals can pass the disease on to their children but generally suffer no ill effects from it themselves. Newborn screening also can detect the disease, and it is already available in several states in the U.S. and in other countries.
If a SMA diagnosis is strongly suspected and genetic testing results are negative or unclear, other diagnostic tests may include electromyography, nerve conduction velocity studies, and muscle biopsy — the standard diagnostic methods before DNA testing became widely available.
Genetic testing is the most accurate way of diagnosing SMA. It involves taking a blood sample from the patient and checking for known mutations associated with the condition.
The standard DNA test for SMA looks for the abnormal absence of exon 7 in both copies of the SMN1 gene — which is the cause of 95% of cases of the main types of SMA. Of note, exons are the sections of a gene that contain instructions for protein production.
The remaining 5% of cases will show a deletion of exon 7 in one SMN1 copy and a different mutation in the other copy of the SMN1 gene. As such, the presence of only one exon 7 in a person with suspected disease should prompt a more comprehensive analysis of the SMN1 gene to detect other potential disease-causing mutations.
The number of copies of a “backup” SMN2 gene, which influence disease severity, also can be measured in a genetic test, which may help to confirm or predict the type of disease. Typically, a higher number of SMN2 copies is associated with less severe disease.
Mutations in genes other than SMN1 — such as IGHMBP2, VAPB, DYNC1H1, BICD2, AR, and UBA1 — cause rarer types of SMA and are not part of standard DNA tests. However, these tests may be requested if a diagnosis is strongly suspected and DNA testing for SMN1 is negative.
DNA testing also can identify SMA carriers, individuals who will not develop SMA but carry one mutated copy of a disease-causing gene and could pass it on to their children. Such information may help inform family planning decisions, as it can aid in evaluating the individual’s chances of having a child affected by SMA. It also may help to determine whether other family members may have inherited the disease.
If both parents carry one mutated copy of SMN1, they will have a 25% chance of having a biological child with any of the most common SMA types. There also is a 50% risk of each of their biological children also being a carrier of the disease.
This type of testing also can be done to identify carriers of the rarer types of SMA, with the chances of having an affected child being calculated according to the mode of inheritance of each type.
Prenatal testing and newborn screening
Genetic testing also can be done before birth to see if an unborn baby has a known SMA-causing mutation. At about 10 weeks of pregnancy, a placenta sample may be used for these tests, while the liquid surrounding the fetus may be collected and analyzed at about 15 weeks (just past three months) of gestation.
Newborn screening for SMA typically involves collecting a blood spot from a heel prick shortly after a baby is born and analyzing it for the absence of exon 7 in both SMN1 copies. As of June 2021, 37 U.S. states had newborn screening available for SMA, covering 85% of all annual births. Other countries have also implemented or are in the process of introducing SMA to the list of diseases screened at birth for free. Rarer types of SMA are currently not included in any newborn screening program.
Electromyography (EMG) is a test that assesses the health of muscles and the motor neurons that control them by measuring the muscles’ electric activity, or response, when motor neurons are stimulated. Motor neurons send out electrical signals to muscles, which in turn contract and give off these signals, which can be measured.
The test involves the insertion of a needle-like electrode into the muscle, and the recording of its electrical signals. This will help determine whether the muscle remains inactive when not stimulated, and whether it is responding appropriately to stimulation when the patient is asked to slowly contract the muscle.
The insertion of the needle-like electrode can cause similar pain to receiving an injection, while the electrical current that is sent through the needle also can cause discomfort to the patient. Patients or their parents can ask technicians to take a short break as a way to mitigate any pain or discomfort during the procedure.
Nerve conduction tests
A nerve conduction test is almost always performed along with an EMG. It uses electrode stickers applied to the surface of the skin at various points over a nerve to measure the speed and strength of electrical signals traveling through that nerve.
One or more electrodes deliver mild electric pulses to the nerve, while the others record the nerve’s responses. These typically will be slower than normal in people with SMA, due to nerve damage. The test may cause a mild tingling feeling.
When EMG tests and nerve conduction studies are done together, they help assess whether symptoms are due to motor nerve impairment, muscle disease, or problems with nerve-to-muscle signal transmission.
A muscle biopsy involves the collection of a small section of muscle tissue — usually from the upper thigh — and its examination under a microscope to see whether it has SMA-associated features. These may include the absence of nerve supply and signs of many cycles of nerve loss and restoration.
Following the application of a local anesthetic, and depending of the amount of sample needed, the healthcare provider may insert a biopsy needle into the muscle, or make a small cut in the skin and into the muscle to collect the tissue.
Some local pain and discomfort can be felt on the skin and muscle involved in the biopsy, but physicians can help relieve the pain by prescribing appropriate medication.
Last updated: July 14, 2021
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